Hepatitis C virus (HCV) is a blood-borne, hepatotropic RNA virus with a high propensity for chronic infection that can progress to cirrhosis and liver cancer. HCV persistence is a significant health problem particularly among U.S. veterans with increased seroprevalence. Consistent with a role for T cells in the viral infections, HCV persists with a dysfunctional virus-specific effector T cell response while HCV-associated liver disease progression is accelerated in the setting of HIV-associated CD4 T cell dysfunction. Based on emerging literature and our own preliminary data, we hypothesize that HIV-associated immune dysregulation results in heightened HCV- specific effector T cell dysfunction through immune inhibitory signals either directly through the costimulatory receptors (e.g. PD-1, CTLA-4) or indirectly by the induction of immune regulatory T cells and cytokines. We also propose that targeted inhibition of these pathways can enhance virus-specific effector function. To this end, the following 3 specific aims will examine if: 1) Chronic evolution with the loss of HCV-specific T cell effector function correlates with increased inhibitory costimulatory receptor expression and regulatory T cell frequency in patients with acute hepatitis C with and without HIV coinfection; 2) Immune inhibitory pathways are accentuated in HIV/HCV coinfected patients compared to HCV monoinfected patients with clinical consequence; 3) HCV-specific effector T cell dysfunction in HIV/HCV-infected patients can be reversed by blocking negative costimulatory and regulatory pathways. The proposed studies will provide insights to underlying immunological mechanisms of T cell dysfunction in HCV-infected patients with HIV coinfection, with potential therapeutic implications. Potential Impact on Veterans Health Care HCV is highly prevalent among U.S. veterans, contributing to significant morbidity and mortality due to chronic hepatitis C, progressive liver cirrhosis and liver cancer development. HIV coinfection markedly increases the morbidity and mortality in HCV-infected patients. The proposed studies (using samples from both veteran and non-veteran subjects) will provide insights to underlying mechanisms of T cell dysfunction and the impact of HIV-associated immune dysfunction in HCV pathogenesis, relevant for immunotherapeutic development that can benefit HCV-infected veterans. PUBLIC HEALTH RELEVANCE: Potential Impact on Veterans Health Care HCV is highly prevalent among U.S. veterans, contributing to significant morbidity and mortality due to chronic hepatitis C, progressive liver cirrhosis and liver cancer development. HIV coinfection markedly increases the morbidity and mortality in HCV- infected patients. The proposed studies (using samples from both veteran and non- veteran subjects) will provide insights to underlying mechanisms of T cell dysfunction and the impact of HIV-associated immune dysfunction in HCV pathogenesis, relevant for immunotherapeutic development that can benefit HCV-infected veterans.